tbuckley/cabot-search huggingface dataset:
Abstract 5862: Racial disparities in pancreatic cancer: A quantitative proteo-genomic analysis
Authors: Digonto Chatterjee, Jack Hester, Meera Srivastava, Alakesh Bera
Journal: Cancer Research (2022)

Abstract Pancreatic cancer remains a major health concern, being among the most deadly forms of cancer. It is the seventh most common cancer, yet it is the third leading cause of cancer deaths in the United States. It is estimated that in 2021, 48,220 patients will die from pancreatic cancer. Risk factors for pancreatic cancer include smoking, diabetes, obesity, chronic pancreatitis, and family history. Over 80% of the patients present with metastatic disease. Despite advances in chemotherapy, the average survival remains less than 5 years even after surgery. Genetic research on pancreatic cancer has generally only focused on familial pancreatic cancer, which is only 10% of all pancreatic cancer patients. This study focuses on finding genes that impact the survival of pancreatic cancer patients based on race, with the goal of finding genes that are race specific and can be used as biomarkers and potential targets to develop personalized treatment options. All datasets for pancreatic cancer in cBioPortal were used for this study. The data were then stratified based on race information for the patients. Three (3) racial categories, 1) White 2) African American and Black, and 3) Asian were chosen. Our analysis finds that White, African Americans and Asians have distinct copy number alterations, more specifically amplifications in specific genes, with GATA6, RECQL4, and MIB1 being only altered in White patients, PKD1L1, GARS1, and NEUROD6 only altered in Black &amp; African American patients, and the entire 4p16.3 cytoband of genes (39 in total), only altered in Asian patients. Patients with alterations in these unique genes also had poor survival. Using the Protein Atlas, MD Anderson Cell Lines Project (MCLP) dataset and genecards.org data, we identified potential drug candidates that target the proteins encoded by these genes. Our study clearly demonstrates that race specific genetic alterations exist in pancreatic cancer and provides a foundation for the development of race specific diagnostic/prognostic biomarkers and targeted therapeutic options with better survival outcomes. Citation Format: Digonto Chatterjee, Jack Hester, Meera Srivastava, Alakesh Bera. Racial disparities in pancreatic cancer: A quantitative proteo-genomic analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5862.
Abstract 3030: Integrated in vitro and in silico screening of breast cancer reveals serine metabolism as a precision oncology target
Authors: Mark Daniel Slayton, Abhinav Achreja, Jin Heon Jeon, Liwei Bao, Alisa Liu, Mason Collard, Deepak Nagrath, Sofia Merajver
Journal: Cancer Research (2022)

Abstract Cellular metabolism sits at the forefront of growth and has been identified as an essential element for the progression of cancer. Large-scale chromosomal alterations and mutations incurred by cancerous cells can predispose cancer cells to dysfunctional metabolic programming independent of microenvironmental pressure. Cancer cells are adaptable to this reprogramming and find alternative measures to sustain elevated metabolic demands. However, this process reduces the number of functional metabolic pathways. Dysregulated metabolic pathways within cancerous cells create an opportunity for therapeutic intervention by targeting genetic chokepoints within these pathways. We analyzed metabolic landscape of breast cancers by combining genomic and transcriptomic data from cancer patient datasets, to identify metabolic pathways prone to dysregulation due to genomic influence. Our platform identified disruption in the serine biosynthesis, which some cancerous cells rely upon to sustain elevated growth in a subset of breast carcinoma. We utilized gain- and loss-of-function techniques in multiple breast cancer cell lines to recapitulate metabolic disruption observed in tumors. These in vitro screens are complemented by metabolic flux analysis and stable-isotope tracer analysis that reveal the vulnerable metabolic pathways in breast cancers with dysregulated serine metabolism. Our data demonstrate that specific metabolic targets can be identified through this integrated screening and validated empirically to confirm their significance as avenues for potential therapeutics. Citation Format: Mark Daniel Slayton, Abhinav Achreja, Jin Heon Jeon, Liwei Bao, Alisa Liu, Mason Collard, Deepak Nagrath, Sofia Merajver. Integrated in vitro and in silico screening of breast cancer reveals serine metabolism as a precision oncology target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3030.
Abstract 5656: Design and development of novel anticancer dimethoxyquinazoline-4-amine analog, DW-8, against colorectal cancer
Authors: Rabin Neupane, Saloni Malla, Mariam Sami Abou-Dahech, Swapnaa Balaji, Shikha Kumari, Yuan Tang, Chandrabose Karthikeyan, Amit K. Tiwari
Journal: Cancer Research (2022)

Abstract Patients with advanced or metastatic colorectal cancer (CRC) often have poor prognosis and survival. There are ongoing efforts to identify novel molecules to manage advanced and metastatic CRC. Modifications in the quinazoline ring has resulted in effective and clinically approved drugs such as gefitinib, erlotinib, vandetanib among others. We rationalized and synthesized a series of 4-anilinoquinazoline analogues, DW (1-10) and evaluated them for anticancer efficacy in human CRC cell lines (HCT116, HT29, SW620). We identified a lead molecule DW-8, with sub-micromolar potency against CRC lines with selectivity index of DW-8 being &amp;gt;2 folds in CRC cells compared to non-cancerous line, CRL1459. Mechanistically, DW-8 produced significant morphological changes in SW620 cells. This included nuclear condensation, cell shrinkage, blebbing and apoptotic bodies formation which are the hallmarks of apoptosis. We found that the DW-8 induced apoptosis by i) producing cell cycle arrest at G2 phase; ii) activated intrinsic apoptosis as shown by cleaved caspases such as caspase-9, the executioner caspases 3 and 7; iii) produced nuclear fragmentation; and iv) increased the level of reactive oxygen species. We are now synthesizing the analogs of DW-8 and are optimizing the formulations for efficient delivery to CRC tumors in vivo. Overall, our result suggests DW-8 may represent a suitable lead for developing novel compound to treat CRC. Citation Format: Rabin Neupane, Saloni Malla, Mariam Sami Abou-Dahech, Swapnaa Balaji, Shikha Kumari, Yuan Tang, Chandrabose Karthikeyan, Amit K. Tiwari. Design and development of novel anticancer dimethoxyquinazoline-4-amine analog, DW-8, against colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5656.
Abstract 2690: Loss of E-cadherin induces IGF1R activation revealing a targetable pathway in invasive lobular breast carcinoma
Authors: Ashuvinee Elangovan, Laura Savariau, Megan E. Yates, Jagmohan Hooda, Alison M. Nagle, Steffi Oesterreich, Jennifer M. Atkinson, Adrian V. Lee
Journal: Cancer Research (2022)

Abstract Invasive Ductal Carcinoma (IDC) and Invasive Lobular Carcinoma (ILC) are two major subtypes of breast cancer with significant differences in their histological and molecular underpinnings. ILC has a unique loss of E-cadherin (CDH1) which we have previously demonstrated as a negative regulator of the Insulin-like Growth Factor 1 receptor (IGF1R) through a comprehensive analysis of cell line models and tumor samples. We propose that loss of E-cadherin in ILC sensitizes cells to growth factor signaling and thus alters their sensitivity to growth factor signaling inhibitors. To investigate this, we used CRISPR to generate CDH1 knockout (KO) IDC cell lines (MCF7, T47D, ZR75.1) to uncover the mechanism by which E-cadherin loss activates the IGF pathway while also assessing its targetability. CDH1 KO cells exhibited anchorage independent growth in suspension culture and altered p120 catenin localization as observed in ILC tumors. Through in vitro studies, we show increased signaling sensitivity to IGF/insulin ligands and enhanced signaling duration in CDH1 KO cells. In addition, we observed a higher migratory potential of CDH1 KO cells compared to wild type (WT) cells, which was further enhanced as a chemotactic response to IGF1 or serum. Further, this phenotype could be reversed with an IGF1R inhibitor, BMS-754807. We additionally identified an increase in Collagen I haptotaxis in the CDH1 KO cells, which was also translated into a novel invasive phenotype towards serum in the T47D CDH1 KO cells. Despite no significant differences in membranous IGF1R levels between WT and CDH1 KO cells, higher ligand-receptor interaction was observed with CDH1 KO cells, demonstrating an increased ligand-receptor complex formation upon stimulation. Our results suggest that loss of CDH1 results in an increase in IGF1 receptor availability for ligand binding which in turn allows for an enhanced downstream signaling activation. Interestingly, a physical repression of E-cadherin on IGF1R could not be demonstrated, suggesting spatial changes on the membrane following E-cadherin loss may control ligand binding. Critically, increased sensitivity to IGF1R, PI3K, AKT and MEK inhibitors was observed in CDH1 KO cells suggesting that these targets should be further explored in ILC and that CDH1 loss may be exploited as a biomarker of response, or for patient stratification to inhibitors targeting these pathways. Citation Format: Ashuvinee Elangovan, Laura Savariau, Megan E. Yates, Jagmohan Hooda, Alison M. Nagle, Steffi Oesterreich, Jennifer M. Atkinson, Adrian V. Lee. Loss of E-cadherin induces IGF1R activation revealing a targetable pathway in invasive lobular breast carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2690.
Abstract 96: A novel virus-drug combination to enhance oncolysis in colorectal cancer (crc)
Authors: Valery A. Chavez, Floritza Bustamante, Abner Murray, Ashok Saluja, Jaime Merchan
Journal: Cancer Research (2022)

Abstract Background: While advances in immune and targeted therapies improve outcomes in selected cancers, only a minority of colorectal cancer (CRC) patients benefit from them. Oncolytic viruses (OVs) represent novel cancer biotherapies, and among them, the oncolytic measles virus (MV) has demonstrated safety and antitumor activity in early clinical studies. MV alone does is not associated with cancer cures. Triptolide, a diterpenoid epoxide extracted from the thunder god vine (Tripterygium wilfordii), has been reported to have potent antitumor effects via multiple mechanisms, including anti-proliferative, pro-apoptotic, antiangiogenic, and induction of ER stress. The effects of triptolide on viral colon cancer oncolysis have not been previously investigated. Objectives: To characterize the in vitro and in vivo mechanisms of novel stromal retargeted oncolytic MVs and improve efficacy by combining MVs with triptolide. Methods: The in vitro effects of triptolide alone, MV-GFP (Edmonston strain of Measles virus expressing eGFP, for human cancer cells), MV-m-uPA (MV retargeted against the murine uPA receptor, for murine cancer cells), or virus-triptolide combinations on tumor cell cytotoxicity were assessed by cell count (Vi cell counter) or xCelligence assays, on HT-29, HCT116, SW620, CT26, and MC38 cells. Molecular and mechanistic characterization of Triptolide’s effects alone and combination with MV in HT29 cells will be analyzed by the (Reverse Phase Protein Array (RPPA) and validated by western blot analysis (experiment undergoing). In vivo effects (tumor progression and survival) of minnelide (M) (water-soluble version of Triptolide) alone and in combination with Measles Virus were assessed in Balb/C mice bearing CT26. Results: While MV and T had dose-dependent cytotoxic activity as single agents, significant augmentation of MV oncolysis was induced by co-treatment with triptolide. In vivo experiments showed similar effects observed in vitro, with potent antitumor activity of triptolide and enhanced in vivo antitumor activity when minnelide was combined with MV vectors. Conclusions: our results strongly suggest that triptolide or minnelide enhances measles virus oncolysis in vitro and in vivo models of colorectal cancer. In vitro and in vivo mechanistic studies are underway to characterize the molecular mechanisms by which triptolide enhances MV oncolysis and will be presented at the meeting. Citation Format: Valery A. Chavez, Floritza Bustamante, Abner Murray, Ashok Saluja, Jaime Merchan. A novel virus-drug combination to enhance oncolysis in colorectal cancer (crc) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 96.
Abstract 1949: Circulating tumor cells presence shorten the cancer specific survival in colorectal cancer: 10 years follow-up study
Authors: Josef Srovnal, Pavel Skalicky, Alona Rehulkova, Kamil Vyslouzil, Monika Vidlarova, Jana Vrbkova, Marian Hajduch
Journal: Cancer Research (2022)

Abstract Introduction: Colorectal cancer (CRC) is one of the most common cancers worldwide and metastases-related death is the main cause of its high mortality. Circulating/disseminated tumor cells (CTCs/DTCc) are considered as precursors of distant metastatic spread and can act as an independent prognostic biomarker. The impact of CTCs/DTCs presence in perioperative period on long-term cancer specific survival (CSS) was assessed. Patients and methods: The presence of CTCs/DTCs in peripheral blood, tumor-draining blood, and bone marrow of 188 colorectal cancer patients was analyzed before, immediately after, and one month after surgery using quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) to detect the carcinoembryonic antigen (CEA) and cytokeratin 20 (CK20) mRNA-positive CTCs. The trial was registered at ClinicalTrials.gov (NCT 03337347), patients were followed-up and the cause of death was determined. Results: Over a median follow-up period of 116.5 months, 81 of 148 (54.7%) stage I-III CRC patients died. In total, 40.7% of them (33/81) died of cancer. The presence of CTCs/DTCs did not correlate with any conventional clinical or pathological features (tumor node metastasis (TNM) stage, grade, KRAS mutations or microsatellite instability). Patients with CTCs/DTCs in the peripheral blood and bone marrow one month after surgery had significantly shorter CSS (p=0.013, HR=2.6; resp. p=0.019, HR=2.3) than those without CTCs/DTCs. Shorter overall survival was also observed in patients with tumor-draining blood CEA mRNA-positive CTCs before surgery (p=0.014). Conclusion: The presence of CK20 mRNA-positive CTCs/DTCs in blood and bone marrow after surgery was confirmed as an independent negative prognostic factor for the long-term cancer-specific survival in stage I-III colorectal cancer patients.The study was supported by Ministry of Health of the Czech Republic (NV18-03-00470), Ministry of Education, Youth and Sport of the Czech Republic (LM2018132; LM2018133), Palacky University Olomouc (LF 2021_019) and European Regional Development Fund (ENOCH CZ.02.1.01/0.0/0.0/16_019/0000868, ACGT CZ.02.1.01/0.0/0.0/16_026/0008448). Citation Format: Josef Srovnal, Pavel Skalicky, Alona Rehulkova, Kamil Vyslouzil, Monika Vidlarova, Jana Vrbkova, Marian Hajduch. Circulating tumor cells presence shorten the cancer specific survival in colorectal cancer: 10 years follow-up study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1949.
Abstract 902: Identification, characterization, and targeting of desmoplastic small round cell tumor cancer stem cell-like cells
Authors: Justin W. Magrath, Alifiani B. Hartono, Sean B. Lee
Journal: Cancer Research (2022)

Abstract Desmoplastic Small Round Cell Tumor (DSRCT) is a rare and aggressive form of pediatric cancer caused by a translocation between chromosomes 11 and 22, creating the novel EWSR1-WT1 fusion gene. Current therapy including surgery and the P6 chemotherapy regimen is insufficient, leading to a 5-year survival rate of only 15-25%. One potential explanation for this poor prognosis is the existence of a cancer stem cell (CSC) population with the ability to resist chemotherapy and cause both tumor recurrence and metastasis. While a CSC population has been identified in the closely related Ewing Sarcoma, most commonly caused by the EWSR1-FLI1 fusion gene, no CSC population has yet been identified in DSRCT. In this study, novel culture conditions were developed that enabled the formation of tumorspheres in vitro in the two commonly available DSRCT cell lines: JN-DSRCT-1 and BER-DSRCT. These novel culture conditions led to upregulation of stemness genes at the RNA and protein level including NANOG and SOX2, two genes that are associated with poor survival outcomes in TCGA sarcomas data. CCK-8 assay demonstrated an increased chemoresistance for tumorspheres versus normal adherent culture especially for doxorubicin, which was confirmed by reduction in PARP cleavage. This chemoresistance may be partially explained by a more quiescent CSC state as shown by reduced cell proliferation and a lower percentage of cells in the S and G2/M phases. However, cells grown in tumorspheres still robustly formed tumors in vivo, thus demonstrating the two hallmark CSC traits of chemoresistance and tumor formation. RNA-seq was performed to elucidate key differences between the adherent and sphere culture conditions and identify potential targets for the therapeutically important CSC-like population. Overrepresentation analysis and gene set enrichment analysis both showed upregulation of pathways related to chromatin assembly and disassembly, suggesting epigenetic changes as DSRCT cells move to a more stem-like state. RNA-seq further revealed kinases upregulated in tumorspheres including B-lymphocyte kinase (BLK) which previous studies have demonstrated is oncogenic, regulated by EWSR1-WT1, and not necessary for normal survival. BLK knockdown reduced CSC-like properties including abrogation of tumorsphere formation and reduction in the levels of SOX2 and NANOG. Together, this work for the first time identifies a CSC-like population in DSRCT and BLK as a potential DSRCT CSC target. Citation Format: Justin W. Magrath, Alifiani B. Hartono, Sean B. Lee. Identification, characterization, and targeting of desmoplastic small round cell tumor cancer stem cell-like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 902.
Abstract 5389: Exploring potential predictive biomarkers for the responsiveness to CTX-712 by in vivo drug sensitivity analysis on PDX models
Authors: Daisuke Morishita, Shigehiro Yagishita, Akio Mizutani, Hiroko Yamakawa, Shunsuke Ebara, Akinobu Hamada
Journal: Cancer Research (2022)

Abstract Cancer’s remarkable diversity had been understood through a logical framework of six key hallmarks. Additionally, several equally prevalent hallmarks have been identified in recent analyses of cellular phenotypes as the stress phenotypes of cancers. A novel hallmark of cancer RNA deregulation has been newly proposed as another hallmark of cancer within this group of stress phenotypes. However, the development of cancer therapies targeting RNA deregulation has only just begun. Indeed, small molecules that attack the RNA maturation processes and produce aberrant RNA are currently under development. We developed orally available, selective, and a first-in-class pan- CDC-like kinase (CLK) inhibitor, CTX-712, currently in phase 1 clinical trials for advanced, relapsed or refractory malignant cancers. CTX-712 dephosphorylates serine and arginine-rich proteins and induces primarily skipped exon type of splicing changes, resulting in the generation of RNA deregulation stress. In multiple preclinical models, excessive RNA deregulation stress caused cancer cell death and tumor growth inhibition. To explore the patient selection biomarkers for CTX-712, in vivo efficacy survey analysis has been conducted on breast, ovarian, colorectal, pancreatic, gastric and lung cancer models from patient derived xenograft (PDX) library with a detailed clinical information. Besides the efficacy investigation, the preclinical pharmacokinetics (PK) and pharmacodynamics (PD) analysis on tested PDX models were also performed to confirm plasma/tumor PK and PD (target CLK inhibition in xenografted tumors). Importantly, tested PDX models could be divided to sensitive (T/C on the most sensitive model = -71.1) and insensitive (T/C on the least sensitive model = 67.7), and the correlated tendency was observed between the efficacy and the inhibition magnitude of intratumor PD marker, production of exon skipped aberrant mRNA. To clarify the differences of sensitivity among tested PDXs will lead us to identity patient selection biomarkers of CTX-712. Therefore, whole transcriptome RNA sequencing, exome sequencing, and other approaches have been applied to reveal the differences of sensitivity among tested PDXs. Through this study on multiple PDXs, integration of drug responsiveness, and genomic/transcriptomic profiling may provide prediction markers for treatment responsiveness of CTX-712. Citation Format: Daisuke Morishita, Shigehiro Yagishita, Akio Mizutani, Hiroko Yamakawa, Shunsuke Ebara, Akinobu Hamada. Exploring potential predictive biomarkers for the responsiveness to CTX-712 by in vivo drug sensitivity analysis on PDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5389.